ONOO- Activatable Fluorescent Sulfur Dioxide Donor for a More Accurate Assessment of Cell Ferroptosis.

Ferroptosis is critical in the treatment of tumor therapies. Thus, monitoring reactive oxygen species (ROS) is of great significance for accurate assessment in ferroptosis without any interference. However, current probes for monitoring ROS during ferroptosis suffer from a drawback in that the probes consume ROS during detection, which inhibits the ferroptosis process and thus affects the accuracy and effectiveness of monitoring the process of ferroptosis. Herein, a new fluorescent donor probe, TFMU-SO2D, with the combination of the moiety of the SO2 donor is designed and synthesized by introducing the aryl boronate moieties that could give it the ability to effectively recognize ONOO-. The released SO2 could consume excess glutathione and regulate oxidative stress by elevating ROS levels, which would offset the ROS depletion by TFMU-SO2D and ensure accuracy in monitoring the ferroptosis process. The experimental results demonstrated that TFMU-SO2D possessed satisfactory performance for monitoring ONOO- as well as simultaneously releasing SO2 in oxidative stress stimulated by monensin and ferroptosis stimulated by erastin and RSL3. Additionally, the capability of SO2 synergized with ferroptosis to inhibit the viability of cancer cells was demonstrated by the CCK8 assay, which may be due to the fact that SO2 can potentiate ferroptosis cell death by increasing the ROS level. Overall, these combined results indicated that TFMU-SO2D possesses the excellent ability to precisely monitor ONOO- during ferroptosis without interference, which is significant for accurately accessing ferroptosis, cancer treatment, and drug development.

HOCl-Activated Reactive Organic Selenium Delivery Platform for Alleviation of Inflammation.

Selenium plays an important role in the biological system and can be used to treat various types of diseases. However, the current selenium delivery systems face the problems of low activity of released Se-containing compounds or nonspecific toxicity of reactive organic selenium donors in living systems. In response to these problems, we constructed a reactive organic selenium delivery platform by the activation of HOCl. Compared with prodrugs without activation capability, the hypochloroselenoite derivatives released from the present platform after activation displayed higher reactivity and could react with various nucleophiles to participate in specific life processes. Taking the selected compound (DHU-Se1) as an example, we found that it could alleviate the process of inflammation by blocking the polarization of macrophages from M0 to M1. Therefore, the development of this system is of great significance for expanding the application of selenium-containing compounds and treating related diseases.

Visualization of peroxynitrite in cyclophosphamide-induced oxidative stress by an activatable probe.

Oxidative stress is considered to be one of the main contributors of cyclophosphamide (CP)-induced toxicity, and the generation of free radicals will cause the interruption of multiple signal transduction pathways. Peroxynitrite (ONOO-) has strong oxidation and nitrification ability and is considered as an indirect indicator of oxidative stress. Therefore, it is necessary to design a fluorescent probe that can detect ONOO- and monitor CP-induced oxidative stress during chemotherapy. Herein, we synthesized a lipid droplet targeting fluorescent probe SX-1 based on triphenylamine-benzoindocyanine. When ONOO- is added to the probe SX-1, the CC bond in the probe is broken, thereby releasing fluorescence. The good spectral response characteristics enable SX-1 to successfully track the fluctuations of ONOO- in living cells. Most importantly, we provided the first visual evidence that the level of ONOO- in HeLa cells was up-regulated under CP induction. All results indicated that SX-1 has great potential in detecting drug-induced ONOO-, and provided a new detection tool for a deeper understanding of drug-induced organism injury.

Telomere length changes after umbilical cord blood transplant.

BACKGROUND: The establishment of donor-derived hematopoiesis in the recipients of hematopoietic stem cell (HSC) transplants involves extensive proliferation and differentiation of HSCs. Data from long-term survivors of HSC transplants suggest that these transplanted HSCs may experience a debilitating replicative senescence. A significant posttransplant shortening of peripheral blood mononuclear cell (PBMNC) telomeres has been observed in both marrow transplant and peripheral blood progenitor cell transplant recipients. Similar studies have not been performed for umbilical cord blood (UCB) HSC transplants, which might be expected to exhibit increased posttransplant replicative potential due to their inherently greater telomere length. STUDY DESIGN AND METHODS: Blood was obtained from donor-recipient pairs of allogeneic PBHSC transplant and UCB HSC transplant, both before transplant and at follow-up treatments (minimum 1 year after transplant) after engraftment. Telomere restriction fragment length (TRFL) analysis was performed on the blood samples. The mean TRFL and posttransplant changes in the mean TRFL were analyzed. RESULTS: Measurements of telomere lengths in the PBMNCs of transplant patients revealed a significant net decrease in telomere length in all transplant recipients compared with their respective donors. Our results also revealed that the PBMNCs of umbilical cord stem cell transplant patients retain a significantly longer posttransplant telomere length. CONCLUSION: The significantly longer telomeres observed in the allogeneic UCB HSC transplant recipients compared to the allogeneic PBHSC transplant recipients in our study may be indicative of a replicative advantage inherent in the use of UCB HSC for transplant.

[Six novel mutations in PAH gene detected by sequencing].

OBJECTIVE: To explore new mutation in phenylalanine hydroxylase (PAH) gene. METHODS: The PAH genes from 40 phenylketonuria (PKU) patients and 30 normal controls were screened by PCR-single strand conformation polymorphism (SSCP) and further sequencing. RESULTS: Eleven mutations and 3 polymorphisms in PAH gene were found. No abnormalities in the PAH gene from 30 controls were detected. CONCLUSION: M276K, M276R, 280insT, IVS10nt+32T-->A, IVS4nt+47C-->T were demonstrated as novel mutations in comparison with the PAH mutation database. One mission mutation (H290R) was first documented in Chinese PKU gene.